Use of dronedarone for the preparation of a medicament for use in the prevention of cardiovascular hospitalization or of mortality

ABSTRACT

Methods of using dronedarone or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for use in the prevention of cardiovascular hospitalization or of mortality, articles of manufacture and packages related thereto.

This application is a divisional of U.S. patent application Ser. No.12/425,125, filed Apr. 16, 2009, which is incorporated herein byreference in its entirety.

The present invention relates to the use of dronedarone orpharmaceutically acceptable salts thereof, for the preparation of amedicament for use in the prevention of cardiovascular hospitalizationand/or of mortality.

2-n-Butyl-3-[4-(3-di-n-butylaminopropoxy)benzoyl]-5-methylsulphonamidobenzofuran,or dronedarone, and pharmaceutically acceptable salts thereof aredescribed in European Patent EP 0 471 609 B1.

Dronedarone blocks potassium, sodium and calcium channels and also hasanti-adrenergic properties.

Dronedarone is an anti-arrhythmic that is effective in maintaining sinusrhythm in patients presenting with atrial fibrillation or atrialflutter.

The applicant has clinically proven that dronedarone significantlyreduces cardiovascular hospitalizations and/or mortality in patientshaving a history of atrial fibrillation or of atrial flutter, by virtueof its ability to modulate the blood potassium level in a safe andeffective way.

In fact, the use of benzofuran derivatives to reduce post-infarctionmortality in patients having a reduced left ventricular function aftermyocardial infarction, without any rhythm disorder requiring ananti-arrhythmic treatment, is known from Patent Applications WO 98/40067and WO 97/34597.

However, these applications neither disclose nor suggest the use ofdronedarone to reduce cardiovascular hospitalizations and mortality inpatients having a history of atrial fibrillation or atrial flutter, inparticular by virtue of its ability to modulate the potassium level inthe blood.

Potassium is the principal intracellular ion and plays an essential rolein physiology.

Specifically, this ion is the principal osmotically active intracellularion and plays an important role in the regulation of intracellularvolume.

A constant and stable potassium concentration is essential for thefunction of enzyme systems and also for good growth and cell division.

Potassium contributes to establishing the resting potential of the cellmembrane and, consequently, changes in potassium concentration, inparticular in the extracellular compartment, have effects on cellexcitability in the nervous, muscle and cardiac system.

A decrease in potassium concentration is known to increase cardiachyperexcitability at the ventricular level, which can result in serious,potentially deadly, rhythm disorders.

The deleterious role of a decrease in potassium concentration has beendocumented in disparate clinical situations.

For example, in patients suffering from heart failure, the decrease inpotassium concentration can lead to deadly rhythm disorders; diureticshaving a “potassium sparing” effect have demonstrated a beneficialeffect in this population.

The rapid decrease in potassium concentrations occurring following theabrupt arrest of intense physical exercise could also be responsible forcertain sudden deaths.

A possible contribution of the decrease in potassium concentrations hasbeen mentioned in the sudden death of patients treated withantipsychotics and also in acute alcohol withdrawal syndromes.

Eating habits with a reduced potassium intake may lead to sudden deathin predisposed individuals, even without any structural cardiacpathology.

The risk of fatal cardiac hyperexcitability is particularly great inpatients who receive an anti-arrhythmic treatment which prolongs theduration of cell repolarization, such as sotalol (Sotalex®). Theseagents may in fact induce a torsade de pointe, which is a severe andpotentially deadly ventricular tachycardia. Torsades de pointes arefacilitated by the decrease in potassium concentration.

Finally, it has been shown that the decrease in potassium concentrationinduces atrial fibrillations (Manoach M., J. Mol. Cell. Cardiol., 1998,30(6): A4[8]).

Another clinical situation where the risk of potentially fatal cardiacrhythm disorders is high is represented by patients treated withdiuretics, these medicaments, which are widely prescribed in manyindications, the most common being arterial hypertension, but also heartfailure, renal insufficiency, nephrotic syndrome, cirrhosis andglaucoma, expose the patient to the risk of a decrease in potassiumconcentration except for “potassium sparing” diuretics.

A complication of the decrease in potassium concentration subsequent totreatment with diuretics may be sudden death, in particular in patientswho present an impairment of the contractile function of the heart orleft ventricular dysfunction or after a myocardial infarction.

Regulation of the potassium concentration could therefore play animportant beneficial role, in particular in the population of patientswho require an anti-arrhythmic treatment (for atrial fibrillation) andwho possibly have other risk factors.

Now, no anti-arrhythmic, to date, in therapy, has shown effects withregard to the regulation of the potassium level in the blood.

Atrial fibrillation (AF) affects about 2.3 million people in NorthAmerica and 4.5 million people in the European Union and is emerging asa growing public health concern because of the aging of the population.

AF is a condition in which the upper chambers of the heart beat in anuncoordinated and disorganized fashion, resulting in a very irregularand fast rhythm (i.e., an irregularly, irregular heartbeat). When bloodis not completely pumped out of the heart's chambers, it can pool andclot. If a blood clot forms in the atria, exits the heart and blocks anartery in the brain, a stroke results. Consequently, about 15 percent ofstrokes result from AF.

AF is increasingly frequent with advancing age and is often caused byage-related changes in the heart, physical or psychological stress,agents that stimulate the heart, such as caffeine, or as a result ofcardiovascular disease. The number is expected to double in the next 20years. Without appropriate management, AF can lead to seriouscomplications, such as stroke and congestive heart failure.

It is known that atrial fibrillation itself can cause changes in theelectrical parameters of the heart known as electrical remodelling andin the structure of the cardiac chambers known as structural remodellingwhich tend to decrease the chances of the patient to get back intonormal sinus rhythm. This vicious circle whereby “atrial fibrillationbegets atrial fibrillation” has been well documented since the 1990s(Wijffels M C, Kirchhof C J, Dorland R, Allessie M A. Atrialfibrillation begets atrial fibrillation. A study in awake chronicallyinstrumented goats. Circulation. 1995 Oct. 1; 92(7):1954-68.). Itexplains why when patients have been in atrial fibrillation for a longtime they develop permanent atrial fibrillation with little or no chanceto recover from this arrhythmia which becomes chronic.

A subject of the present invention is therefore the use of dronedaroneor a pharmaceutically acceptable salt thereof, for the preparation of amedicament, wherein said medicament is taken, for use in the preventionof cardiovascular hospitalizations and/or of mortality.

Said prevention of cardiovascular hospitalizations and/or of mortalityis provided to patients having a history of atrial fibrillation oratrial flutter.

A subject of the present invention is therefore the use of dronedaroneor a pharmaceutically acceptable salt thereof, for the preparation of amedicament for use in the prevention of cardiovascular hospitalizationsand/or of mortality notably in patients having a history of atrialfibrillation or atrial flutter.

A subject of the present invention is specifically the use ofdronedarone or a pharmaceutically acceptable salt thereof, for thepreparation of a medicament for use in the prevention of cardiovascularhospitalizations and/or of mortality notably in patients having ahistory of atrial fibrillation or atrial flutter through regulation ofthe potassium level in the blood.

Mention may in particular be made of cardiovascular mortality, and moreparticularly sudden death, also called sudden cardiac death or suddendeath from cardiovascular causes.

A subject of the present invention is also the use of dronedarone or apharmaceutically acceptable salt thereof, for the preparation of amedicament, taken twice a day with a meal, for use in the prevention ofmortality and/or of cardiovascular hospitalizations notably in patientshaving a history of atrial fibrillation or atrial flutter

More specifically, a subject of the present invention is the use ofdronedarone or a pharmaceutically acceptable salt thereof, for thepreparation of a medicament for use in the prevention of approximately24% of cardiovascular hospitalizations and/or of mortality in patientshaving a history of atrial fibrillation or atrial flutter, by regulatingthe potassium level in the blood.

A subject of the present invention is also the use of dronedarone or apharmaceutically acceptable salt thereof, for the preparation of amedicament for use in the prevention of approximately 25% ofcardiovascular hospitalizations and/or of cardiovascular mortality inpatients having a history of atrial fibrillation or atrial flutter, byregulating the potassium level in the blood.

A subject of the present invention is also the use of dronedarone or apharmaceutically acceptable salt thereof, for the preparation of amedicament for use in the prevention of approximately 26% ofcardiovascular hospitalizations and/or of sudden death in patientshaving a history of atrial fibrillation or atrial flutter, by regulatingthe potassium level in the blood.

A subject of the present invention is also the use of dronedarone or apharmaceutically acceptable salt thereof, in patients having a historyof atrial fibrillation or atrial flutter, for the preparation of amedicament for use in the prevention:

-   -   of cardiovascular hospitalizations, and more particularly of        approximately 25% of cardiovascular hospitalizations, and/or    -   of mortality, particularly of approximately 15% of mortality,        and more particularly of approximately 16% of mortality, and/or    -   of cardiovascular mortality, and more particularly of        approximately 30% of cardiovascular mortality, and/or    -   of arrhythmic death, and more particularly of approximately 45%        of arrhythmic death.    -   of sudden death, and more particularly of approximately 59% of        sudden death and/or

Another subject of the instant invention is the use of dronedarone orone of its pharmaceutically acceptable salts for the preparation of amedicament for use in the prevention of cardiovascular hospitalizationand/or of mortality notably in patients with permanent atrialfibrillation or atrial flutter.

More precisely, the invention relates to the use of dronedarone or oneof its pharmaceutically acceptable salts for the preparation of amedicament for the prevention of about 33% of cardiovascularhospitalization and/or of mortality notably in patients with permanentatrial fibrillation or atrial flutter.

Another subject of the instant invention is the use of dronedarone orone of its pharmaceutically acceptable salts for the preparation of amedicament for use in the prevention of cardiovascular hospitalizationand/or of mortality notably in patients with a history of atrialfibrillation or atrial flutter and with structural heart diseaseparticularly structural heart disease in a stable hemodynamic condition.

More precisely, the invention relates to the use of dronedarone or oneof its pharmaceutically acceptable salts for the preparation of amedicament for the prevention of about 24% of cardiovascularhospitalization and/or of mortality notably in patients with a historyof atrial fibrillation or atrial flutter and with structural heartdisease in a stable hemodynamic condition.

More precisely, the invention relates to the use of dronedarone or oneof its pharmaceutically acceptable salts for the preparation of amedicament for use in the prevention of about 24% of cardiovascularhospitalization notably in patients with a history of atrialfibrillation or atrial flutter and with structural heart disease in astable hemodynamic condition.

More precisely, the invention relates to the use of dronedarone or oneof its pharmaceutically acceptable salts for the preparation of amedicament for use in the prevention of about 24% of mortality notablyin patients with a history of atrial fibrillation or atrial flutter andwith structural heart disease in a stable hemodynamic condition.

More precisely, the invention relates to the use of dronedarone or oneof its pharmaceutically acceptable salts for the preparation of amedicament for use in the prevention of about 33% of cardiovascularmortality notably in patients with a history of atrial fibrillation oratrial flutter and with structural heart disease in a stable hemodynamiccondition.

Said structural heart disease may be coronary heart disease and/orIschemic dilated cardiomyopathy and/or non-ischemic dilatedcardiomyopathy and/or rheumatic valvular heart disease and/ornon-rheumatic valvular heart disease and/or hypertrophic cardiomyopathyand/or LVEF <45% and/or history of congestive heart failure whereincongestive heart failure may be defined for example as NYHA class III orby a reduced left ventricular ejection fraction below 0.35.

NYHA means New York Heart Association.

Mention may be made that congestive heart failure is a sub-group ofheart failure.

Thus, the subject of the instant invention is also the use ofdronedarone or one of its pharmaceutically acceptable salts for thepreparation of a medicament for use in the prevention of cardiovascularhospitalization and/or of mortality notably in patients with a historyof atrial fibrillation or atrial flutter and with congestive heartfailure in a stable hemodynamic condition.

In an embodiment, the subject of the instant invention is the use ofdronedarone or one of its pharmaceutically acceptable salts for thepreparation of a medicament for use in the prevention of cardiovascularhospitalization and/or of mortality notably in patients with a historyof atrial fibrillation or atrial flutter and with congestive heartfailure defined as NYHA class III in a stable hemodynamic condition.

In an embodiment, the subject of the instant invention is the use ofdronedarone or one of its pharmaceutically acceptable salts for thepreparation of a medicament for use in the prevention of cardiovascularhospitalization and/or of mortality notably in patients with a historyof atrial fibrillation or atrial flutter and with congestive heartfailure defined by a reduced left ventricular ejection fraction below0.35 in a stable hemodynamic condition.

More precisely, the invention relates to the use of dronedarone or oneof its pharmaceutically acceptable salts for the preparation of amedicament for use in the prevention of about 44% of cardiovascularhospitalization and/or of mortality notably in patients with a historyof atrial fibrillation or atrial flutter and with congestive heartfailure defined as NYHA class III in a stable hemodynamic condition.

More precisely, the invention relates to the use of dronedarone or oneof its pharmaceutically acceptable salts for the preparation of amedicament for use in the prevention of about 32% of cardiovascularhospitalization and/or of mortality notably in patients with a historyof atrial fibrillation or atrial flutter and with congestive heartfailure defined by a reduced left ventricular ejection fraction below0.35 in a stable hemodynamic condition.

In an embodiment, the invention relates to the use of dronedarone or oneof its pharmaceutically acceptable salts for the preparation of amedicament for use in the prevention of mortality notably in patientswith a history of atrial fibrillation or atrial flutter and withcongestive heart failure in a stable hemodynamic condition.

More precisely, the invention relates to the use of dronedarone or oneof its pharmaceutically acceptable salts for the preparation of amedicament for use in the prevention of about 34% of mortality notablyin patients with a history of atrial fibrillation or atrial flutter andwith congestive heart failure defined as NYHA class III in a stablehemodynamic condition.

More precisely, the invention relates to the use of dronedarone or oneof its pharmaceutically acceptable salts for the preparation of amedicament for use in the prevention of about 45% of death in patientswith a history of atrial fibrillation or atrial flutter and withcongestive heart failure defined with a left ventricular ejectionfraction below 0.35 in a stable hemodynamic condition.

In an embodiment, the invention relates to the use of dronedarone or oneof its pharmaceutically acceptable salts for the preparation of amedicament for use in the prevention of the worsening or development ofcongestive heart failure notably in patients with a history of atrialfibrillation or atrial flutter.

More precisely, the invention relates to the use of dronedarone or oneof its pharmaceutically acceptable salts for the preparation of amedicament for use in the prevention of about 22% of the worsening ordevelopment of congestive heart failure NYHA class IV in patients with ahistory of atrial fibrillation or atrial flutter.

Patients with heart failure in a stable hemodynamic condition may bedefined as patients without heart failure in an unstable hemodynamiccondition.

In general, patients with heart failure in an unstable hemodynamiccondition may be defined as patients with a severe heart failure andsaid severe heart failure may be defined by any of the following:

-   -   worsening symptoms of heart failure at rest or with minimal        exertion or,    -   history of, or current symptoms of congestive heart failure at        rest or,    -   symptoms of heart failure with minimal exertion within the last        month, i.e. the month prior to start of treatment or,    -   hospitalization for heart failure within the last month, i.e.        the month prior to start of treatment,    -   NYHA Class IV,    -   NYHA Class III within the last month,    -   recent decompensation as indicated by the need for        hospitalization or intravenous therapy, for example intravenous        inotropic or diuretic therapy,    -   recent decompensation requiring hospitalization or intravenous        therapy for the treatment of heart failure.

Therefore, the invention also relates to the use of dronedarone orpharmaceutically acceptable salts thereof for preparing a medicament foruse in the treatment of atrial fibrillation or flutter or for use in theprevention of mortality and/or of cardiovascular hospitalization inpatients without severe heart failure.

A subject of the instant invention also relates to dronedarone or one ofits pharmaceutically acceptable salts for the treatment of atrialfibrillation or flutter in patients without severe heart failure, atherapeutic amount of dronedarone or pharmaceutically acceptable saltthereof being administered.

In one embodiment, the invention relates to dronedarone or one of itspharmaceutically acceptable salts for the treatment of atrialfibrillation or flutter in patients without severe heart indicated byone or more of the following:

a) a history of, or current symptoms of congestive heart failure;b) symptoms of heart failure with minimal exertion within the lastmonth;c) hospitalization of the patient for heart failure within the lastmonth;d) hospitalization of the patient for NYHA Class IV heart failure;e) hospitalization of the patient for NYHA Class III heart failurewithin the last month,f) hospitalization of the patient for heart failure with recentdecompensation as indicated by the need for hospitalization orintravenous therapy; andg) hospitalization of the patient for heart failure with recentdecompensation requiring hospitalization or intravenous therapy for thetreatment of heart failure.

In another embodiment, the invention relates to dronedarone or one ofits pharmaceutically acceptable salts for the treatment of atrialfibrillation or flutter in patients without severe heart failureindicated by hospitalization of the patient for NYHA Class IV heartfailure.

In another embodiment, the invention relates to dronedarone or one ofits pharmaceutically acceptable salts for the treatment of atrialfibrillation or flutter in patients without severe heart failureindicated by hospitalization of the patient for NYHA Class III heartfailure within the last month, i.e., one month prior to administrationof dronedarone or one of its pharmaceutically acceptable salts.

Another subject of the invention is performed by providing dronedaroneor pharmaceutically acceptable salts thereof, wherein said dronedaroneor pharmaceutically acceptable salts thereof is provided along withinformation indicating that dronedarone or pharmaceutically acceptablesalts thereof is indicated in patients with a recent history of orcurrent atrial fibrillation or flutter and without severe heart failure.

In one embodiment, the information indicates that the atrialfibrillation or flutter is non-permanent. In another embodiment, theinformation indicates that the atrial fibrillation or flutter isassociated with at least one risk factor. In another embodiment, theinformation indicates that severe heart failure is indicated by symptomsof heart failure with minimal exertion within the last month. In anotherembodiment, the information indicates that severe heart failure isindicated by hospitalization for heart failure within the last month. Inanother embodiment, the information indicates that severe heart failureis indicated by a history of, or current symptoms of congestive heartfailure at rest. In another embodiment, the information indicates thatsevere heart failure is indicated by hospitalization of the patient forNYHA Class IV heart failure. In another embodiment, the informationindicates that severe heart failure is indicated by hospitalization ofthe patient for NYHA Class III heart failure within the last month. Inanother embodiment, the information indicates that severe heart failureis indicated by hospitalization of the patient for heart failure withrecent decompensation as indicated by the need for hospitalization orintravenous therapy.

In an embodiment of the invention, the information comprises printedmatter that advises that dronedarone or pharmaceutically acceptablesalts thereof is indicated in patients with either a recent history ofor current atrial fibrillation or flutter with associated risk factorsand without severe heart failure. In another embodiment, the printedmaterial is a label.

The term “providing” includes selling, distributing, shipping, offeringfor sell, importing etc.

Mention may be made that “dronedarone for the treatment of” may beunderstood as “use of dronedarone for the preparation of a medicamentfor use in the treatment of”.

The treatment of atrial fibrillation or flutter with dronedarone or apharmaceutically acceptable salt thereof may be contra-indicated forpatients with severe heart failure as indicated by any of the following:

-   -   worsening symptoms of heart failure at rest or with minimal        exertion or,    -   history of, or current symptoms of congestive heart failure at        rest or,    -   symptoms of heart failure with minimal exertion within the last        month, i.e. the month prior to start of treatment or,    -   hospitalization for heart failure within the last month, i.e.        the month prior to start of treatment,    -   NYHA Class IV,    -   NYHA Class III within the last month,    -   recent decompensation as indicated by the need for        hospitalization or intravenous therapy, for example intravenous        inotropic or diuretic therapy,    -   recent decompensation requiring hospitalization or intravenous        therapy for the treatment of heart failure.

The invention also relates to the use of dronedarone or pharmaceuticallyacceptable salts thereof for preparing a medicament for use in thetreatment of atrial fibrillation or flutter or for use in the preventionof mortality and/or of cardiovascular hospitalizations wherein saidmedicament is contra-indicated for patients with severe heart failure asindicated by any of the following:

-   -   worsening symptoms of heart failure at rest or with minimal        exertion or,    -   history of, or current symptoms of congestive heart failure at        rest or,    -   symptoms of heart failure with minimal exertion within the last        month, i.e. the month prior to start of treatment or,    -   hospitalization for heart failure within the last month, i.e.        the month prior to start of treatment,    -   NYHA Class IV,    -   NYHA Class III within the last month,    -   recent decompensation as indicated by the need for        hospitalization or intravenous therapy, for example intravenous        inotropic or diuretic therapy,    -   recent decompensation requiring hospitalization or intravenous        therapy for the treatment of heart failure.

The invention also relates to a method of promoting the use ofdronedarone or pharmaceutically acceptable salts thereof, the methodcomprising the step of conveying to a recipient at least one messageselected from the group consisting of:

(a) dronedarone or pharmaceutically acceptable salts thereof should beprescribed to a patient who has not been diagnosed with severe heartfailure;(b) dronedarone or pharmaceutically acceptable salts thereof iscontraindicated in patients with a history of or current symptoms ofcongestive heart failure;(c) dronedarone or pharmaceutically acceptable salts thereof iscontraindicated in patients with severe heart failure;(d) dronedarone or pharmaceutically acceptable salts thereof iscontraindicated in patients with symptoms of heart failure with minimalexertion within the last month; and(e) dronedarone or pharmaceutically acceptable salts thereof iscontraindicated in patients who were hospitalized for heart failurewithin the last month,(f) dronedarone or pharmaceutically acceptable salts thereof iscontraindicated in patients who were hospitalized for NYHA Class IVheart failure,(g) dronedarone or pharmaceutically acceptable salts thereof iscontraindicated in patients who were hospitalized for NYHA Class IIIheart failure within the last month,(h) dronedarone or pharmaceutically acceptable salts thereof iscontraindicated in patients who were hospitalized for heart failure withrecent decompensation as indicated by the need for hospitalization orintravenous therapy, for example intravenous inotropic or diuretictherapy,(i) dronedarone or pharmaceutically acceptable salts thereof iscontraindicated in patients who were hospitalized for heart failure withrecent decompensation requiring hospitalization or intravenous therapyfor the treatment of heart failure.

The invention also relates to a method of promoting the use ofdronedarone or a pharmaceutically acceptable salt thereof, the methodcomprising the step of conveying to a recipient at least one messageselected from the group consisting of

-   -   a) a primary endpoint of a study of dronedarone, or a        pharmaceutically acceptable salt thereof, was the time to first        hospitalization for cardiovascular reasons or death from any        cause;    -   b) a secondary endpoint of a study of dronedarone, or        pharmaceutically acceptable salt thereof, was death from any        cause;    -   c) a secondary endpoint of a study of dronedarone, or a        pharmaceutically acceptable salt thereof, was time to death from        any cause;    -   d) a secondary endpoint of a study of dronedarone, or a        pharmaceutically acceptable salt thereof, was time to        cardiovascular death;    -   e) a secondary endpoint of a study of dronedarone, or a        pharmaceutically acceptable salt thereof, was time to first        hospitalization for cardiovascular reasons;    -   f) a secondary endpoint of a study of dronedarone, or a        pharmaceutically acceptable salt thereof, was time to first        hospitalization for atrial fibrillation and other        supraventricular rhythm disorders;    -   g) a secondary endpoint of a study of dronedarone, or a        pharmaceutically acceptable salt thereof, was time to first        hospitalization for worsening heart failure;    -   h) a secondary endpoint of a study of dronedarone, or a        pharmaceutically acceptable salt thereof, was time to first        hospitalization for myocardial infarction;    -   i) a secondary endpoint of a study of dronedarone, or a        pharmaceutically acceptable salt thereof, was time to first        hospitalization for myocardial infarction;    -   j) a secondary endpoint of a study of dronedarone, or a        pharmaceutically acceptable salt thereof, was time to first        hospitalization for transient ischemic event or cerebral stroke;    -   k) a secondary endpoint of a study of dronedarone, or a        pharmaceutically acceptable salt thereof, was time to sudden        death;    -   l) dronedarone, or a pharmaceutically acceptable salt thereof,        reduced the combined endpoint of cardiovascular hospitalization        or death from any cause by about 24 percent;    -   m) dronedarone, or a pharmaceutically acceptable salt thereof,        reduced the combined endpoint of cardiovascular hospitalization        or death from any cause by 24.2 percent;    -   n) dronedarone, or a pharmaceutically acceptable salt thereof,        reduced the combined endpoint of cardiovascular hospitalization        or death from any cause by 24.2 percent, driven by a reduction        in cardiovascular hospitalization; and    -   o) 70 percent of patients enrolled in a study of dronedarone, or        a pharmaceutically acceptable salt thereof, had no heart        failure.

In one embodiment, the message is provided in a label or package insert.

The invention also concerns an article of manufacture comprising

a) a packaging material;b) dronedarone or pharmaceutically acceptable salts thereof, andc) a label or package insert contained within the packaging materialindicating that dronedarone or pharmaceutically acceptable salts thereofis contraindicated in patients with severe heart failure.

In some embodiments, the packaging material indicates that dronedaroneor pharmaceutically acceptable salts thereof is contraindicated inpatients with severe heart failure indicated by one or more of thefollowing:

a) a history of, or current symptoms of congestive heart failure;b) symptoms of heart failure with minimal exertion within the lastmonth;c) hospitalization of the patient for heart failure within the lastmonth;d) hospitalization of the patient for NYHA Class IV heart failure;e) hospitalization of the patient for NYHA Class III heart failurewithin the last month,f) hospitalization of the patient for heart failure with recentdecompensation as indicated by the need for hospitalization orintravenous therapy; andg) hospitalization of the patient for heart failure with recentdecompensation requiring hospitalization or intravenous therapy for thetreatment of heart failure.

The invention also relates to a package comprising dronedarone orpharmaceutically acceptable salts thereof and a label, said labelcomprising a printed statement which informs a prospective user thatdronedarone or pharmaceutically acceptable salts thereof iscontraindicated in patients with severe heart failure.

In some embodiments, the printed statement informs a prospective user ofone or more of the following:

a) that dronedarone or pharmaceutically acceptable salts thereof iscontraindicated in patients with severe heart failure indicated by ahistory of, or current symptoms of congestive heart failure;b) that dronedarone or pharmaceutically acceptable salts thereof iscontraindicated in patients with severe heart failure indicated bysymptoms of heart failure with minimal exertion within the last month;c) that dronedarone or pharmaceutically acceptable salts thereof iscontraindicated in patients with severe heart failure indicated byhospitalization for heart failure within the last month;d) that dronedarone or pharmaceutically acceptable salts thereof iscontraindicated in patients with severe heart failure indicated by NYHAClass IV;e) that dronedarone or pharmaceutically acceptable salts thereof iscontraindicated in patients with severe heart failure indicated by NYHAClass III within the last month;f) that dronedarone or pharmaceutically acceptable salts thereof iscontraindicated in patients with severe heart failure indicated byrecent decompensation as indicated by the need for hospitalization orintravenous therapy, for example intravenous inotropic or diuretictherapy; andg) dronedarone or pharmaceutically acceptable salts thereof iscontraindicated in patients who were hospitalized for heart failure withrecent decompensation requiring hospitalization or intravenous therapyfor the treatment of heart failure.

The invention also relates to a package comprising dronedarone or apharmaceutically acceptable salt thereof and a label, said labelcomprising at least one message selected from the group consisting of:

-   -   a) a primary endpoint of a study of dronedarone, or a        pharmaceutically acceptable salt thereof, was the time to first        hospitalization for cardiovascular reasons or death from any        cause; and    -   b) a secondary endpoint of a study of dronedarone, or        pharmaceutically acceptable salt thereof, was death from any        cause;    -   c) a secondary endpoint of a study of dronedarone, or a        pharmaceutically acceptable salt thereof, was time to death from        any cause;    -   d) a secondary endpoint of a study of dronedarone, or a        pharmaceutically acceptable salt thereof, was time to        cardiovascular death;    -   e) a secondary endpoint of a study of dronedarone, or a        pharmaceutically acceptable salt thereof, was time to first        hospitalization for cardiovascular reasons;    -   f) a secondary endpoint of a study of dronedarone, or a        pharmaceutically acceptable salt thereof, was time to first        hospitalization for atrial fibrillation and other        supraventricular rhythm disorders;    -   g) a secondary endpoint of a study of dronedarone, or a        pharmaceutically acceptable salt thereof, was time to first        hospitalization for worsening heart failure;    -   h) a secondary endpoint of a study of dronedarone, or a        pharmaceutically acceptable salt thereof, was time to first        hospitalization for myocardial infarction;    -   i) a secondary endpoint of a study of dronedarone, or a        pharmaceutically acceptable salt thereof, was time to first        hospitalization for myocardial infarction;    -   j) a secondary endpoint of a study of dronedarone, or a        pharmaceutically acceptable salt thereof, was time to first        hospitalization for transient ischemic event or cerebral stroke;        and    -   k) a secondary endpoint of a study of dronedarone, or a        pharmaceutically acceptable salt thereof, was time to sudden        death,    -   l) dronedarone, or a pharmaceutically acceptable salt thereof,        reduced the combined endpoint of cardiovascular hospitalization        or death from any cause by about 24 percent;    -   m) dronedarone, or a pharmaceutically acceptable salt thereof,        reduced the combined endpoint of cardiovascular hospitalization        or death from any cause by 24.2 percent;    -   n) dronedarone, or a pharmaceutically acceptable salt thereof,        reduced the combined endpoint of cardiovascular hospitalization        or death from any cause by 24.2 percent, driven by a reduction        in cardiovascular hospitalization; and    -   o) 70 percent of patients enrolled in a study of dronedarone, or        a pharmaceutically acceptable salt thereof, had no heart        failure.

Another method of the invention comprises treating a patient with arecent history of or current atrial fibrillation or flutter, said methodcomprising administrating to said patient a therapeutically effectiveamount of dronedarone, or a pharmaceutically acceptable salt thereof,wherein said patient does not have severe heart failure.

In one embodiment, the patient does not have severe heart failureindicated by one or more selected from the group consisting of:

-   -   a) history of, or current symptoms of congestive heart failure        at rest;    -   b) symptoms of heart failure with minimal exertion within the        last month; and    -   c) hospitalization for heart failure within the last month,    -   d) NYHA Class IV,    -   e) NYHA Class III within the last month,    -   f) recent decompensation as indicated by the need for        hospitalization or intravenous therapy, for example intravenous        inotropic or diuretic therapy,    -   g) recent decompensation requiring hospitalization or        intravenous therapy for the treatment of heart failure.

Another method of the invention relates to transforming a patient with arecent history of or current atrial fibrillation or flutter bydecreasing the patient's risk of cardiovascular hospitalizations ormortality, comprising administrating to said patient a therapeuticallyeffective amount of dronedarone, or a pharmaceutically acceptable saltthereof, wherein said patient does not have severe heart failure.

A subject of the invention is a method of decreasing the risk ofcardiovascular hospitalizations or mortality in a patient having ahistory of atrial fibrillation or atrial flutter, said method comprisingadministering dronedarone, or a pharmaceutically acceptable saltthereof, twice a day with a meal to a patient in need thereof, whereinsaid patient does not have severe heart failure.

In terms of clinical study, the prevention of “cardiovascularhospitalizations or of mortality” or of “cardiovascular hospitalizationsor of cardiovascular mortality” or of “cardiovascular hospitalizationsor of sudden death” constitute what are referred to as compositecriteria or a combined endpoint.

All the percentages given above correspond to average values.

Diuretics are widely prescribed for their efficacy in the treatment of adiversity of conditions, such as arterial hypertension, congestive heartfailure, renal insufficiency, nephrotic syndrome, cirrhosis or glaucoma.

One of the major consequences of a treatment based on diuretics, exceptfor potassium sparing diuretics, is increased potassium excretion whichcan result in hypokalaemia.

Now, hypokalaemia is known to increase cardiac excitability, resulting,in certain patients, in ventricular arrhythmia and sudden death (Cooperet al., Circulation, 1999, 100, pages 1311-1315).

Advantageously, a subject of the present invention is also the use ofdronedarone or a pharmaceutically acceptable salt thereof, for thepreparation of a medicament for use in the prevention of cardiovascularhospitalizations and/or of mortality in patients having a history ofatrial fibrillation or atrial flutter and receiving a diuretic-basedtreatment, in particular a treatment based on non-potassium sparingdiuretics.

A subject of the present invention is also the use of dronedarone or apharmaceutically acceptable salt thereof, for the preparation of amedicament for regulating the potassium level in the blood, inparticular for use in the prevention of hypokalaemia, especially inpatients having histories of atrial fibrillation or atrial flutterand/or patients receiving a diuretic-based treatment, in particular atreatment based on non-potassium sparing diuretics.

Said diuretic is administered at therapeutically active doses chosenbetween 1 mg/day and 2 g/day.

Among the pharmaceutically acceptable salts of dronedarone, mention maybe made of the hydrochloride.

The term “non-potassium sparing diuretic” is intended to mean a diureticwhich increases potassium excretion.

The term “cardiovascular hospitalization” means a hospitalization whichis caused by at least one of the following pathologies (Hohnloser etal., Journal of cardiovascular electrophysiology, January 2008, vol. 19,No. 1, pages 69-73):

-   -   relating to atherosclerosis,    -   myocardial infarction or unstable angina pectoris,    -   stable angina pectoris or atypical thoracic pain,    -   syncope,    -   transient ischemic event or cerebral stroke (except intracranial        haemorrhage),    -   atrial fibrillation and other supraventricular rhythm disorders,    -   non-fatal cardiac arrest,    -   ventricular arrhythmia,    -   cardiovascular surgery, except heart transplant,    -   heart transplant,    -   implantation of a cardiac stimulator (pacemaker), of an        implantable defibrillator (“ICD”) or of another cardiac device,    -   percutaneous coronary, cerebrovascular or peripheral        intervention,    -   variations in arterial pressure (hypotension, hypertension,        except syncope), cardiovascular infection,    -   major bleeding/haemorrhage (requiring two or more blood cell        pellets or any intracranial haemorrhage),    -   pulmonary embolism or deep vein thrombosis,    -   worsening of congestive heart failure including acute pulmonary        oedema or dyspnoea from cardiac causes.

Consequently, the prevention of cardiovascular hospitalization may beunderstood as the prevention of cardiovascular hospitalization for atleast one of the above mentioned pathologies.

Mention may be made of the prevention of cardiovascular hospitalizationfor atrial fibrillation and/or other supraventricular rhythm disorders.

Mention may also be made of the prevention of cardiovascularhospitalization for transient ischemic event or cerebral stroke.

Thus, a subject of the present invention is also the use of dronedaroneor a pharmaceutically acceptable salt thereof, for the preparation of amedicament for the prevention of cardiovascular hospitalization for atleast one of the above mentioned pathologies such as atrial fibrillationand/or other supraventricular rhythm disorders and/or stroke.

The term “mortality” or “death” are equivalent and cover mortality dueto any cause, whether cardiovascular or non-cardiovascular or unknown.

The term “cardiovascular mortality” covers, in the context of theinvention, mortality due to any cardiovascular causes (any death exceptthose due to a non-cardiovascular cause), in particular death from anarrhythmic cause, also called arrhythmic death, and more particularly,sudden death from cardiovascular causes, also called sudden death orsudden cardiac death.

Cardiovascular mortality may be due for example to:

-   -   Aortic dissection/aneurysm    -   Cardiac tamponade    -   Cardiogenic shock    -   congestive heart failure    -   Death during a cardiovascular transcutaneous interventional        procedure or cardiovascular surgical intervention    -   Hemorrhage (except cardiac tamponade)    -   Myocardial infarction or unstable angina (including        complications of myocardial infarction, except arrhythmias)    -   Pulmonary or peripheral embolism    -   Stroke    -   Sudden cardiac death (eg, unwitnessed death or documented        asystole)    -   Ventricular arrhythmia, subclassified as torsades de pointes,        ventricular extrasystole, ventricular fibrillation, ventricular        tachycardia (non-sustained and sustained ventricular        tachycardia), or other ventricular arrhythmia    -   Unknown cause

The term “sudden death” refers, in general, to death occurring withinthe hour or less than one hour after the appearance of new symptoms orunexpected death without warning.

It will also be specified that the expression “patients having a historyof atrial fibrillation or atrial flutter”, “patients with a history ofor a current atrial fibrillation or flutter” or “patients with a recenthistory of or a current atrial fibrillation or flutter” or “patientswith paroxysmal or persistent atrial fibrillation or flutter” or“patients with a history of, or a current paroxysmal or persistentatrial fibrillation or flutter” or “patients with a recent history of,or a current paroxysmal or persistent atrial fibrillation or flutter” or“patients with paroxysmal or intermittent atrial fibrillation or atrialflutter and a recent episode of atrial fibrillation or atrial flutter,who are in sinus rhythm or who will be cardioverted” or “patients withparoxysmal or persistent atrial fibrillation or atrial flutter and arecent episode of atrial fibrillation or atrial flutter, who are insinus rhythm or who will be cardioverted” means a patient who, in thepast, has presented one or more episodes of atrial fibrillation orflutter and/or who is suffering from atrial fibrillation or atrialflutter at the time the dronedarone or a pharmaceutically acceptablesalt thereof is used. More particularly, this expression means patientswith documentation of having been in both atrial fibrillation or flutterand sinus rhythm within the last 6 months preceding the start oftreatment. Patients could be either in sinus rhythm, or in atrialfibrillation or flutter at the time the dronedarone or apharmaceutically acceptable salt thereof is initiated.

It will also be specified that the terms “persistent” and “intermittent”are equivalent.

Patients in “permanent atrial fibrillation or flutter” are patients thathave all scheduled ECGs in this rhythm throughout the period thedronedarone or a pharmaceutically acceptable salt thereof isadministered.

The term “coronary disease” or “coronary heart disease” refers to:

-   -   1) Coronary artery disease: documented history of acute        myocardial infarction and/or significant (≧70%) coronary artery        stenosis and/or history of a revascularization procedure        (percutaneous transluminal coronary angioplasty, stent        implantation in a coronary artery, coronary artery bypass graft,        etc) and/or a positive exercise test and/or positive nuclear        scan of cardiac perfusion    -   2) Ischemic dilated cardiomyopathy: clinically significant left        ventricular dilatation secondary to coronary artery disease

Of course, it may be understood that “prevention of cardiovascularhospitalization and/or mortality” results in the reduction of the riskof cardiovascular hospitalization and or mortality or in the reductionof the need of cardiovascular hospitalization and or mortality.

Among the patients with a recent history of, or a current atrialfibrillation or atrial flutter, mention may be made of patients with arecent history of, or a current, non permanent atrial fibrillation orflutter.

Among the patients, notably patients having a history of atrialfibrillation or atrial flutter, mention may also be made of patientsalso exhibiting at least one of the following risk factors:

-   -   age notably equal to or above 70, or even above 75,    -   hypertension,    -   diabetes,    -   history of cerebral stroke or of systemic embolism, i.e. prior        cerebrovascular accident,    -   left atrial diameter greater than or equal to 50 mm measured for        example by echocardiography,    -   left ventricular ejection fraction less than 40%, measured for        example by two-dimensional echography.

The efficacy of dronedarone to reduce cardiovascular hospitalization ordeath is now clinically proven in patients with the above mentionedassociated risk factors.

The above mentioned risks factors may be defined as cardiovascular riskfactors which are associated to atrial fibrillation.

Among the patients, notably patients having a history of atrialfibrillation or atrial flutter, mention may also be made of patientsalso exhibiting additional risk factors, i.e. at least one of thefollowing pathologies:

-   -   hypertension,    -   underlying structural heart disease,    -   tachycardia,    -   coronary disease,    -   non-rheumatic heart valve disease,    -   dilated cardiomyopathy of ischemic origin,    -   ablation of atrial fibrillation or flutter, for example catheter        ablation or endomyocardial ablation,    -   supraventricular tachycardia other than atrial fibrillation or        flutter,    -   history of heart valve surgery,    -   non-ischemic dilated cardiomyopathy,    -   hypertrophic cardiomyopathy,    -   rheumatic valve disease,    -   sustained ventricular tachycardia,    -   congenital cardiopathy,    -   ablation, for example catheter ablation, for tachycardia other        than for atrial fibrillation or flutter,    -   ventricular fibrillation,        and/or at least one cardiac device chosen from:    -   a cardiac stimulator,    -   an implantable defibrillator (“ICD”).

The expression “regulating the potassium level in the blood” meanspreventing the decrease or a possible increase in said level.

The principal classes of non-potassium sparing diuretics are:

-   -   thiazide diuretics,    -   loop diuretics,    -   proximal diuretics (osmotics, carbonic anhydrase inhibitors).

For their therapeutic use, dronedarone and pharmaceutically acceptablesalts thereof are generally introduced into pharmaceutical compositions.

These pharmaceutical compositions contain an effective dose ofdronedarone or of a pharmaceutically acceptable salt thereof, and alsoat least one pharmaceutically acceptable excipient.

Said pharmaceutical composition may be given once or twice a day withfood.

The dose of dronedarone administered per day, orally, may reach 800 mg,taken in one or more intakes, for example one or two.

More specifically, the dose of dronedarone administered may be takenwith food.

More specifically, the dose of dronedarone administered per day, orally,may reach 800 mg, taken in two intakes with a meal.

The dose of dronedarone administered per day, orally may be taken at arate of twice a day with a meal for example with the morning and theevening meal.

More specifically, the two intakes may comprise same quantity ofdronedarone.

There may be specific cases where higher or lower dosages areappropriate; such dosages do not depart from the context of theinvention. According to the usual practice, the dosage appropriate foreach patient is determined by the physician according to the method ofadministration, the weight, the pathology, the body surface, the cardiacoutput and the response of said patient.

Said excipients are chosen according to the pharmaceutical form and themethod of administration desired, from the usual excipients which areknown to those skilled in the art.

In said pharmaceutical compositions for oral, sublingual, subcutaneous,intramuscular, intravenous, topical, local, intratracheal, intranasal,transdermal or rectal administration, dronedarone, or the salt thereof,can be administered in unit administration form, as a mixture withconventional pharmaceutical excipients, to animals and to humans in thecases mentioned above.

The suitable unit administration forms comprise forms for oraladministration, such as tablets, soft or hard gel capsules, powders,granules and oral solutions or suspensions, sublingual, buccal,intratracheal, intraocular or intranasal administration forms, forms foradministration by inhalation, topical, transdermal, subcutaneous,intramuscular or intravenous administration forms, rectal administrationforms, and implants. For topical application, dronedarone andpharmaceutically acceptable salts thereof can be used in creams, gels,ointments or lotions.

By way of example, a unit administration form of dronedarone or apharmaceutically acceptable salt thereof, in tablet form, may correspondto one of the following examples:

Ingredients mg % Dronedarone hydrochloride (corresponding to 400 mg of426 65.5 base) Methylhydroxypropylcellulose 21.1 3.25 Lactosemonohydrate 46.55 7.2 Maize starch 45.5 7 Polyvinylpyrrolidone 65 10Poloxamer 407 40 6.15 Anhydrous colloidal silica 2.6 0.4 Magnesiumstearate 3.25 0.5 650 100

Ingredients mg % Dronedarone hydrochloride (corresponding to 400 mg of426 65.5 base) Microcrystalline cellulose 65 10 Anhydrous colloidalsilica 2.6 0.4 Anhydrous lactose 42.65 6.6 Polyvinylpyrrolidone 13 2Poloxamer 407 40 6.15 Macrogol 6000 57.5 8.85 Magnesium stearate 3.250.5 650 100

Ingredients mg Dronedarone hydrochloride (corresponding to 400 mg of 426base) Microcrystalline cellulose 26 Maize starch 45.5Polyvinylpyrrolidone 65 Poloxamer 407 40 Anhydrous colloidal silica 3.25Magnesium stearate 3.25 Lactose monohydrate 41.65 650

Ingredients mg Dronedarone hydrochloride (corresponding to 400 mg of 213base) Microcrystalline cellulose 13 Maize starch 22.75Polyvinylpyrrolidone 32.5 Poloxamer 407 20 Anhydrous colloidal silica1.3 Magnesium stearate 1.625 Lactose monohydrate 20.825 650

According to another of its aspects, the present invention also relatesto a method for treating the pathologies indicated above, whichcomprises the administration, to a patient, of an effective dose ofdronedarone or a pharmaceutically acceptable salt thereof.

One method of the invention includes decreasing the risk of mortality,cardiac hospitalizations, or the combination thereof in a patient, saidmethod comprising administering to said patient an effective amount ofdronedarone or a pharmaceutically acceptable salt thereof, with food.

In one embodiment, the mortality is a cardiovascular mortality. In oneembodiment, the mortality is a sudden death.

Another method of the invention is a method of regulating the potassiumlevel in the blood of a patient having a history of or current atrialfibrillation or atrial flutter, said method comprising administering tosaid patient dronedarone or a pharmaceutically acceptable salt thereof,with food.

In some embodiments of the above methods according to the invention, thepatient has a history of or current atrial fibrillation or flutter. Insome embodiments of the above methods according to the invention, thepatient has a recent history of or a current paroxysmal or persistentatrial fibrillation or atrial flutter. In some embodiments of the abovemethods according to the invention, the patient has a history of or acurrent, non permanent atrial fibrillation or atrial flutter. In someembodiments of the above methods according to the invention, theadministration of dronedarone or pharmaceutically acceptable saltthereof prevents cardiovascular hospitalizations. In some embodiments ofthe above methods according to the invention, said patient has apermanent atrial fibrillation or atrial flutter. In some embodiments ofthe above methods according to the invention, said patient hasstructural heart disease. In some embodiments of the above methodsaccording to the invention, said patient has congestive heart failure ina stable hemodynamic condition. In some embodiments of the above methodsaccording to the invention, said patient has congestive heart failuredefined as NYHA class III in a stable hemodynamic condition. In someembodiments of the above methods according to the invention, saidpatient has congestive heart failure defined by a reduced leftventricular ejection fraction below 0.35 in a stable hemodynamiccondition. In some embodiments of the above methods according to theinvention, said patient also exhibits one or more of the above mentionedassociated risk factors.

Another method of the invention is a method of preventing coronarydisease in a patient with a history of or current atrial fibrillation oratrial flutter, said method comprising administrating to said patient atherapeutically effective amount of dronedarone or a pharmaceuticallyacceptable salt thereof. In one embodiment, said patient furtherreceives a diuretic-based treatment. In one embodiment, said patientfurther receives a treatment with a non-potassium-sparing diuretic. Insome embodiments, said patient also exhibits one or more of the abovementioned associated risk factors.

BRIEF DESCRIPTION OF THE DRAWINGS

The present invention is illustrated by the data hereinafter withreference to the attached drawings in which:

FIG. 1 represents a Kaplan Meier curve with the cumulative rate ofhospitalization or of death from any cause over a period of 30 months;

FIG. 2 represents a Kaplan Meier curve with the cumulative rate ofhospitalization or of cardiovascular death over a period of 30 months;

FIG. 3 represents a Kaplan Meier curve with the cumulative rate ofhospitalization or of sudden death over a period of 30 months;

FIG. 4 represents a Kaplan Meier curve with the cumulative rate ofhospitalization over a period of 30 months;

FIG. 5 represents a Kaplan Meier curve with the cumulative rate of deathfrom any cause over a period of 30 months;

FIG. 6 represents a Kaplan Meier curve with the cumulative rate ofcardiovascular death over a period of 30 months;

FIG. 7 represents a Kaplan Meier curve with the cumulative rate ofsudden death over a period of 30 months;

FIG. 8 represents the mean variations in potassium between the first andthe last administration over a period of 30 months.

FIG. 9 represents a Kaplan Meier curve with the cumulative rate ofhospitalization or of death from any cause over a period of 30 months.

FIG. 10 represents a Kaplan Meier curve with the cumulative rate ofhospitalization or of death from any cause in Patients with NYHA classIII congestive heart failure over a period of 30 months.

The efficacy, relative to a placebo, of dronedarone and ofpharmaceutically acceptable salts thereof, in the prevention ofcardiovascular hospitalizations or of mortality was demonstrated, bymeans of dronedarone hydrochloride, in a prospective, multinational,multicentre, double-blind clinical study with random distribution in twogroups of treatment (group treated with dronedarone hydrochloride andgroup treated with a placebo) of patients having a history of atrialfibrillation or atrial flutter.

I. Patient Selection

The patients had to have a history of atrial fibrillation or flutterand/or could be in normal sinus rhythm or in atrial fibrillation orflutter at inclusion.

The patient recruitment was carried out by taking into account thefollowing inclusion criteria:

Inclusion Criteria:

-   -   1) One of the following risk factors had to be present:        -   age equal to or greater than 70 years,        -   hypertension (taking antihypertensives of at least two            different classes),        -   diabetes,        -   history of cerebral stroke (transient ischemic event or            completed cerebral stroke) or of systemic embolism,        -   left atrial diameter greater than or equal to 50 mm measured            by echocardiography,        -   left ventricular ejection fraction less than 40%, measured            by two-dimensional echography;            or    -   age equal to or above 70, or even above 75, possibly combined        with at least one of the risk factors below:        -   hypertension (taking antihypertensives of at least two            different classes),        -   diabetes,        -   history of cerebral stroke (transient ischemic event or            completed cerebral stroke) or of systemic embolism,        -   left atrial diameter greater than or equal to 50 mm measured            by echocardiography,        -   left ventricular ejection fraction less than 40%, measured            by two-dimensional echography;    -   2) availability of an electrocardiogram carried out during the        past 6 months in order to document the presence or the history        of atrial fibrillation or flutter;    -   3) availability of an electrocardiogram carried out during the        past 6 months in order to document the presence or absence of        normal sinus rhythm.

Exclusion Criteria: General Criteria:

-   -   Refusal or inability to give informed consent to participate in        the study.    -   Any non cardiovascular illness or disorder that could preclude        participation or severely limit survival including cancer with        metastasis and organ transplantation requiring immune        suppression.    -   Pregnant women (pregnancy test must be negative) or women or        childbearing potential not on adequate birth control: only women        with a highly effective method of contraception [oral]        contraception or intra-uterine device (IUD) or sterile can be        randomize.    -   Breastfeeding women.    -   Previous (2 preceding months) or current participation in        another trial with an investigational drug (under development)        or with an investigational device.    -   Previous participation in this trial.

Criteria Related to a Cardiac Condition:

-   -   Patients in permanent atrial fibrillation    -   Patients in unstable hemodynamic condition such as acute        pulmonary edema within 12 hours prior to start of study        medication; cardiogenic shock; treatment with IV pressor agents;        patients on respirator; congestive heart failure of stage NYHA        IV within the last 4 weeks; uncorrected, hemodynamically        significant primary obstructive valvular disease;        hemodynamically significant obstructive cardiomyopathy; a        cardiac operation or revascularization procedure within 4 weeks        preceding randomization    -   Planned major non-cardiac or cardiac surgery or procedures        including surgery for valvular heart disease, coronary artery        bypass graft (CABG), percutaneous coronary intervention (PCI),        or on urgent cardiac transplantation list    -   Acute myocarditis or constrictive pericarditis    -   Bradycardia <50 bpm and/or PR-interval ≧0.28 sec on the last        12-lead ECG.    -   Significant sinus node disease (documented pause of 3 seconds or        more) or 2^(nd) or 3^(rd) degree atrioventricular block        (AV-block) unless treated with a pacemaker.

Criteria Related to Concomitant Medications:

Need of a concomitant medication that is prohibited in this trial,including the requirement for Vaughan Williams Class I and IIIanti-arrhythmic drugs, that would preclude the use of study drug duringthe planned study period, i.e. patients have to stop othersantiarrhythmics such as Vaughan Williams Class I and III anti-arrhythmicdrugs, for example amiodarone, flecainide, propafenone, quinidine,disopyramide, dofetilide, solatol.

Criteria Related to Laboratory Abnormalities:

-   -   Plasma potassium <3.5 mmol/l (as anti-arrhythmic drugs can be        arrhythmogenic in patients with hypokalemia, this must be        corrected prior to randomization.    -   A calculated GFR at baseline <10 ml/min using the Cockroft Gault        formula (GFR [ml/min]=(140−AGE [years]*WEIGHT        [kilograms]*CONSTANT/CREATININE [μmol/L], where CONSTANT is 1        for men and 0.85 for women).

Furthermore, the concomitant use of grapefruit juice and all potentinhibitors of CYP3A4 such as ketoconazole were prohibited.

II. Duration and Treatment

Treatment was initiated using tablets containing either the placebo oran amount of dronedarone hydrochloride corresponding to 400 mg ofdronedarone at a rate of twice a day with the morning and evening mealand more specifically at a rate of one tablet in the morning during orshortly after breakfast and one tablet in the evening during or shortlyafter dinner.

The anticipated duration of the treatment was variable according to thetime at which each patient was included in the study, and could rangefrom a minimum of 12 months for the last patient included up to amaximum corresponding to the entire duration of the study (12months+duration of inclusion), i.e. approximately 30 months for thefirst patients included.

III. Results

The results obtained in this trial were analysed by the Kaplan Meiermethod for the figures, and the relative risk (RR) was estimated usingCox's proportional-effect regression model.

The relative risk (RR) is the ratio of the rates of occurrence of ahospitalization or of a death among the patients on dronedarone,relative to the patients on placebo.

The percentage reduction x of a given event (hospitalization, death,cardiovascular death, etc.) is calculated in the following way:

x=1−relative risk.

III.1. Results Relating to Cardiovascular Hospitalizations and toMortality (Principal Judgement Criterion)

Among the 4628 patients included in the study, 2301 were part of thegroup treated with dronedarone hydrochloride.

917 events were recorded in the placebo group, against 734 in the grouptreated with dronedarone hydrochloride.

The calculated relative risk is 0.758 with a p=2×10⁻⁸, i.e. a reductionin cardiovascular hospitalizations and deaths of 24.2% on dronedaronehydrochloride, the result being highly significant.

FIG. 1, which reproduces the results obtained, shows a clear separationof the two cumulative curves very soon after the beginning of thetreatment, this separation persisting over time throughout the durationof the study.

III.2. Results Relating to Cardiovascular Hospitalizations and toCardiovascular Mortality

Among the 4628 patients included in the study, 2301 were part of thegroup treated with dronedarone hydrochloride.

892 events were recorded in the placebo group, against 701 in the grouptreated with dronedarone hydrochloride.

The calculated relative risk is 0.745 with a p=45×10⁻¹⁰, i.e. areduction in cardiovascular hospitalizations and cardiovascular deathsof 25.5% on dronedarone hydrochloride, the result being highlysignificant.

FIG. 2, which reproduces the results obtained, shows a clear separationof the two cumulative curves very soon after the beginning of thetreatment, this separation persisting over time throughout the durationof the study.

III.3. Results Relating to Cardiovascular Hospitalizations and to SuddenDeath

Among the 4628 patients included in the study, 2301 were part of thegroup treated with dronedarone hydrochloride.

873 events were recorded in the placebo group, against 684 in the grouptreated with dronedarone hydrochloride.

The calculated relative risk is 0.743 with a p=48×10⁻¹⁰, i.e. areduction in cardiovascular hospitalizations and sudden deaths of 25.5%on dronedarone hydrochloride, the result being highly significant.

FIG. 3, which reproduces the results obtained, shows a clear separationof the two cumulative curves very soon after the beginning of thetreatment, this separation persisting over time throughout the durationof the study.

III.4. Results Relating to Cardiovascular Hospitalizations

Among the 4628 patients included in the study, 2301 were part of thegroup treated with dronedarone hydrochloride.

859 events were recorded in the placebo group, against 675 in the grouptreated with dronedarone hydrochloride.

The calculated relative risk is 0.745 with a p=9×10⁻⁹, i.e. a reductionin cardiovascular hospitalizations of 25.5% on dronedaronehydrochloride.

FIG. 4, which reproduces the results obtained, shows a clear separationof the two cumulative curves very soon after the beginning of thetreatment, this separation persisting over time throughout the durationof the study.

III.5. Results Relating to Cardiovascular Hospitalizations for AtrialFibrillation or Supraventricular Arrhythmia

Among the 4628 patients included in the study, 2301 were part of thegroup treated with dronedarone hydrochloride.

457 events were recorded in the placebo group, against 296 in the grouptreated with dronedarone hydrochloride.

The calculated relative risk is 0.616, i.e. a reduction incardiovascular hospitalizations for atrial fibrillation of 38.4%

III.6. Results Relating to Cardiovascular Hospitalizations for TransientIschemic Event or Stroke

Among the 4628 patients included in the study, 2301 were part of thegroup treated with dronedarone hydrochloride.

61 events were recorded in the placebo group, against 43 in the grouptreated with dronedarone hydrochloride.

The calculated relative risk is 0.66 with a p=0.027, i.e. a reduction incardiovascular hospitalizations for transient ischemic event or strokeof 34% on dronedarone hydrochloride.

III.7. Results Relating to Mortality from any Cause

Among the 4628 patients included in the study, 2301 were part of thegroup treated with dronedarone hydrochloride.

139 deaths were recorded in the placebo group, against 116 in the grouptreated with dronedarone hydrochloride.

The calculated relative risk is 0.844 with a p=0.1758, i.e. a reductionof death of 15.6% on dronedarone hydrochloride.

FIG. 5, which reproduces the results obtained, shows a clear separationof the two cumulative curves very soon after the beginning of thetreatment, this separation persisting over time throughout the durationof the study.

III.8. Results Relating to Cardiovascular Mortality

Among the 4628 patients included in the study, 2301 were part of thegroup treated with dronedarone hydrochloride.

94 cardiovascular deaths were recorded in the placebo group, against 65in the group treated with dronedarone hydrochloride.

The calculated relative risk is 0.698 with a p=0.0252, i.e. a reductionin cardiovascular mortality of 30.2% on dronedarone hydrochloride.

FIG. 6, which reproduces the results obtained, shows a clear separationof the two cumulative curves very soon after the beginning of thetreatment, this separation persisting over time throughout the durationof the study.

III.9. Results Relating to Arrhythmic Death

Among the 4628 patients included in the study, 2301 were part of thegroup treated with dronedarone hydrochloride.

48 arrhythmic deaths (deaths from cardiac arrhythmia) were recorded inthe placebo group, against 26 in the group treated with dronedaronehydrochloride.

The calculated relative risk is 0.55 with a p=0.001, i.e. a reduction ofarrhythmic death of 45% on dronedarone hydrochloride.

III.10. Results Relating to Sudden Death

Among the 4628 patients included in the study, 2301 were part of thegroup treated with dronedarone hydrochloride.

35 sudden deaths were recorded in the placebo group, against 14 in thegroup treated with dronedarone hydrochloride.

The calculated relative risk is 0.405 with a p=0.0031, i.e. a reductionin sudden death of 59.5% on dronedarone hydrochloride.

FIG. 7, which reproduces the results obtained, shows a clear separationof the two cumulative curves very soon after the beginning of thetreatment, this separation persisting over time throughout the durationof the study.

III.11. Regulation of the Blood Potassium Level

The potassium concentration-modulating effect is clearly documented inthe study by virtue of the results of analyses of regular blood samplestaken throughout the duration of the study in the context of themonitoring of vital parameters.

The variations in potassium (in mmol/l) between the first and the lastadministration of the medicament of the study are included in FIG. 8, inwhich B signifies basal level, D signifies day and M signifies month.

An analysis of covariance of the change in blood potassium level, takinginto account the starting value during the study after the 24^(th)month, shows a significant different in favour of dronedarone comparedto the placebo (p<0.0001).

Dronedarone therefore makes it possible to regulate the potassium levelin the blood.

III.12. Results Relating to the Patients in the Study Receiving, inAddition, a Diuretic-Based Treatment

The clinical results of the study corroborate the hypothesis thatmodulating potassium decreases the risk of sudden death, in particularin patients exposed to the risk of a decrease in potassium exacerbatedby the administration of a diuretic treatment: the reduction in the riskof sudden death by dronedarone, i.e. the prevention of sudden deathcompared with the placebo, was 70.4% in the patients on diuretics and34% in the patients not taking diuretics.

Furthermore, the reduction in the risk was greater in the groups ofpatients liable to be treated with diuretics, such as hypertensivepatients, where the reduction in the risk was 62%, against a reductionof 45.5% observed in the patients who were not hypertensive.

III.13. Results Relating to Cardiovascular Hospitalizations and toMortality in Patients who Developed “Permanent AtrialFibrillation/Flutter”

Among the 4628 patients included in the study, 2301 were part of thegroup treated with dronedarone hydrochloride.

294 patients who developed permanent atrial fibrillation/flutter in thegroup treated with placebo versus 178 patients in the group treated withdronedarone hydrochloride (p<0.001).

74 events were recorded in the placebo group versus 29 in the grouptreated with dronedarone hydrochloride.

The calculated relative risk is 0.67 with a p=0.06, i.e. a reduction incardiovascular hospitalizations and to mortality in patients withpermanent atrial fibrillation/flutter of 33% on dronedaronehydrochloride.

FIG. 9, which reproduces the results obtained, shows a clear separationof the two cumulative curves very soon after the beginning of thetreatment, this separation persisting over time throughout the durationof the study.

III.14. Results Relating to the Prevention of CardiovascularHospitalization or Death in Patients with a Structural Heart Disease

From the 4628 patients included in the trial, 2301 were part of thegroup treated with dronedarone hydrochloride.

629 events were reported in the placebo group versus 486 in the grouptreated with dronedarone hydrochloride.

Calculated relative risk was equal to 0.76, i.e. a decrease ofcardiovascular hospitalization or death of 24%.

III.15. Results Relating to the Prevention of CardiovascularHospitalization in Patients with a Structural Heart Disease

From the 4628 patients included in the trial, 2301 were part of thegroup treated with dronedarone hydrochloride.

583 events were reported in the placebo group versus 452 in the grouptreated with dronedarone hydrochloride.

Calculated relative risk was equal to 0.76, i.e. a decrease ofcardiovascular hospitalization of 24%.

III.16. Results Relating to the Prevention of Death in Patients with aStructural Heart Disease

From the 4628 patients included in the trial, 2301 were part of thegroup treated with dronedarone hydrochloride.

106 events were reported in the placebo group versus 77 in the grouptreated with dronedarone hydrochloride.

Calculated relative risk was equal to 0.76, i.e. a decrease of death of24%.

III.17. Results Relating to the Prevention of Cardiovascular Death inPatients with a Structural Heart Disease

From the 4628 patients included in the trial, 2301 were part of thegroup treated with dronedarone hydrochloride.

75 events were reported in the placebo group versus 48 in the grouptreated with dronedarone hydrochloride.

Calculated relative risk was equal to 0.67, i.e. a decrease ofcardiovascular deaths of 33%.

III.18. Results Relating to the Prevention of CardiovascularHospitalization and Death in Patients with a Congestive Heart FailureDefined as NYHA Class III in a Stable Hemodynamic Condition

From the 4628 patients included in the trial, 2301 were part of thegroup treated with dronedarone hydrochloride.

At randomization, 109 patients with NYHA class III congestive heartfailure in a stable hemodynamic condition were part of the placebo groupand 91 patients with NYHA class III congestive heart failure in a stablehemodynamic condition were part of the group treated with dronedaronehydrochloride.

71 events were reported in the placebo group versus 40 in the grouptreated with dronedarone hydrochloride.

Calculated relative risk was equal to 0.56, i.e. a decrease ofcardiovascular hospitalization or death of 44%.

FIG. 10 shows that the effect of dronedarone occurred early andincreased over time.

III.19. Results Relating to the Prevention of CardiovascularHospitalization and Death in Patients with Congestive Heart FailureDefined with a Reduced Left Ventricular Ejection Fraction Below 0.35 ina Stable Hemodynamic Condition

From the 4628 patients included in the trial, 2301 were part of thegroup treated with dronedarone hydrochloride.

At randomization, 87 patients with congestive heart failure in a stablehemodynamic condition as defined by a reduced left ventricular ejectionfraction below 0.35 were part of the placebo group and 92 patients withcongestive heart failure in a stable hemodynamic condition defined witha reduced left ventricular ejection fraction below 0.35 were part of thegroup treated with dronedarone hydrochloride.

47 events were reported in the placebo group versus 39 in the grouptreated with dronedarone hydrochloride.

Calculated relative risk was equal to 0.68, i.e. a decrease ofcardiovascular hospitalization or death 32%.

III.20. Results Relating to the Prevention of Death in Patients withCongestive Heart Failure Defined as NYHA Class III

From the 4628 patients included in the trial, 2301 were part of thegroup treated with dronedarone hydrochloride.

At randomization, 109 patients with NYHA class III congestive heartfailure in a stable hemodynamic condition were part of the placebo groupand 91 patients with NYHA class III congestive heart failure in a stablehemodynamic condition were part of the group treated with dronedaronehydrochloride.

21 events were reported in the placebo group versus 12 in the grouptreated with dronedarone hydrochloride.

Calculated relative risk was equal to 0.66, i.e. a decrease of death of34%.

III.21. Results Relating to the Prevention of Death in Patients withCongestive Heart Failure in a Stable Hemodynamic Condition as Defined bya Reduced Left Ventricular Ejection Fraction Below 0.35

From the 4628 patients included in the trial, 2301 were part of thegroup treated with dronedarone hydrochloride.

At randomization, 87 patients with congestive heart failure in a stablehemodynamic conditions defined by a reduced left ventricular ejectionfraction below 0.35 were part of the placebo group and 92 patients withcongestive heart failure in a stable hemodynamic condition as defined bya reduced defined with a left ventricular ejection fraction below 0.35were part of the group treated with dronedarone hydrochloride.

16 events were reported in the placebo group versus 10 in the grouptreated with dronedarone hydrochloride.

Calculated relative risk was equal to 0.55, i.e. a decrease of death of45%.

III.22. Results Relating to the Prevention of Death in Patients withCongestive Heart Failure in a Stable Hemodynamic Condition as Defined asNYHA Class III and by a Reduced Left Ventricular Ejection Fraction Below0.35

Dronedarone 400 mg Placebo BID (N = 23) (N = 24) Number of events, n 1913 Median survival 254.0 [131.0; 487.0 [182.0; NA] [95% Cl](day) 293.0]Cumulative incidence of 0.348 [0.153; 0.292 [0.110; 0.474] events at 6months 0.542] [95% Cl] Cumulative incidence of 0.696 [0.508; 0.375[0.181; 0.569] events at 1 year [95% Cl] 0.884] Cumulative incidence0.837 [0.680; 0.578 [0.368 ; 0.788] of events at 2 years 0.993] [95% Cl]Endpoint's composition: Cardiovascular 15 10 hospitalization Death fromany cause 4 3 - Cardiovascular death 3 2 - Non cardiovascular death 1 1Log-rank test p-value 0.0711 Relative risk [95% Cl]a 0.523 [0.256;1.070]III.23. Results Relating to the Prevention of HospitalizationsAssociated with Congestive Heart Failure, that is for Patients whoDeveloped Congestive Heart Failure

From the 4628 patients included in the trial, 2301 were part of thegroup treated with dronedarone hydrochloride.

132 events were reported in the placebo group versus 112 in the grouptreated with dronedarone hydrochloride.

Calculated relative risk was equal to 0.855, i.e. a decrease ofcardiovascular hospitalization associated with congestive heart failureof 14.5%.

III.24. Results Relating to the Prevention of HospitalizationsAssociated with Class IV Congestive Heart Failure, that is for Patientswho Developed Congestive Heart Failure

From the 4628 patients included in the trial, 2301 were part of thegroup treated with dronedarone hydrochloride.

54 events were reported in the placebo group versus 42 in the grouptreated with dronedarone hydrochloride.

Calculated relative risk was equal to 0.78, i.e. a decrease ofcardiovascular hospitalization associated with class IV congestive heartfailure of 22%.

III.25. Results Relating to the Prevention of CardiovascularHospitalization or Death in Patients with Coronary Heart Disease

From the 4628 patients included in the trial, 2301 were part of thegroup treated with dronedarone hydrochloride.

At randomization, 737 patients with coronary heart disease were part ofthe placebo group and 668 patients with coronary heart disease were partof the group treated with dronedarone hydrochloride.

350 events were reported in the placebo group versus 252 in the grouptreated with dronedarone hydrochloride.

Calculated relative risk was equal to 0.733, i.e. a decrease ofcardiovascular hospitalization or death of 27% in patients with coronaryheart disease (P=0.0002).

III.26. Results Relating to the Prevention of CardiovascularHospitalization for Patients with Coronary Heart Disease

From the 4628 patients included in the trial, 2301 were part of thegroup treated with dronedarone hydrochloride.

At randomization, 737 patients with coronary heart disease were part ofthe placebo group and 668 patients with coronary heart disease were partof the group treated with dronedarone hydrochloride.

321 events were reported in the placebo group versus 233 in the grouptreated with dronedarone hydrochloride.

Calculated relative risk was equal to 0.740, i.e. a decrease ofcardiovascular hospitalization of 26% for patients with coronary heartdisease (P=0.0005).

III.27. Results Relating to the Prevention of Death for Patients withCoronary Heart Disease

From the 4628 patients included in the trial, 2301 were part of thegroup treated with dronedarone hydrochloride.

At randomization, 737 patients with coronary heart disease were part ofthe placebo group and 668 patients with coronary heart disease were partof the group treated with dronedarone hydrochloride.

66 events were reported in the placebo group versus 39 in the grouptreated with dronedarone hydrochloride.

Calculated relative risk was equal to 0.643, i.e. a decrease of death of36% for patients with coronary heart disease (P=0.0273).

III.28. Results Relating to the Prevention of Cardiovascular Death forPatients with Coronary Heart Disease

From the 4628 patients included in the trial, 2301 were part of thegroup treated with dronedarone hydrochloride.

At randomization, 737 patients with coronary heart disease were part ofthe placebo group and 668 patients with coronary heart disease were partof the group treated with dronedarone hydrochloride.

47 events were reported in the placebo group versus 26 in the grouptreated with dronedarone hydrochloride.

Calculated relative risk was equal to 0.602, i.e. a decrease ofcardiovascular death of 40% (P=0.0355).

III.29. Results Relating to the Prevention of CardiovascularHospitalization and Death in Patients with Cardiovascular Risk Factors

N HR (95% Cl) Age ≧ 75 years 1925 0.75 (0.65, 0.87) Hypertension 39950.77 (0.69, 0.85) Diabetes 945 0.75 (0.61, 0.91) Prior cerebrovascularaccident 616 0.80 (0.62, 1.02) or systemic embolism Left atriumdiameter >= 50 mm 955 0.77 (0.63, 0.94) LVEF < 0.40 338 0.72 (0.51,1.00)

Consequently, these results show a decrease of respectively 25%, 23%,25%, 20%, 23%, 28% of cardiovascular hospitalization and death inpatients with at least one of each above cardiovascular risk factors.

III.30. Results Relating to the Prevention of CardiovascularHospitalization

Placebo Dronedarone (N = 2327) (N = 2301) HR (95% Cl) Any cardiovascular859 (36.9%) 675 (29.3%) 0.745 hospitalization [0.673-0.824]Atherosclerosis re- 8 (0.3%) 11 (0.5%) 1.282 lated (if not other-[0.516-3.187] wise specified) Myocardial 61 (2.6%) 48 (2.1%) 0.742infarction or [0.508-1.083] unstable angina Stable angina 41 (1.8%) 45(2.0%) 1.042 pectoris or atypical [0.682-1.591] chest pain Syncope 24(1.0%) 21 (0.9%) 0.836 [0.465-1.501] TIA or stroke 35 (1.5%) 28 (1.2%)0.751 (except [0.457-1.235] intracranial hemorrhage) Atrial fibrillation457 (19.6%) 296 (12.9%) 0.616 and other supra- [0.532-0.713] ventricularrhythm disorders Non-fatal 2 (<0.1%) 3 (0.1%) 1.442 cardiac arrest[0.241-8.632] Cardiovascular 23 (1.0%) 21 (0.9%) 0.852 surgery[0.472-1.540] except cardiac transplantation Implantation of a 29 (1.2%)32 (1.4%) 1.041 pacemaker, ICD or [0.630-1.721] any other cardiac deviceTranscutaneous 31 (1.3%) 27 (1.2%) 0.817 coronary, [0.488-1.369]cerebrovascular or peripheral procedure Blood pressure 21 (0.9%) 21(0.9%) 0.949 related [0.518-1.738] (hypotension, hypertension; exceptsyncope) Cardiovascular 0 (0%) 4 (0.2%) NA infection Major bleeding 24(1.0%) 21 (0.9%) 0.816 (requiring two or [0.454-1.466] more units ofblood or any intracranial hemorrhage) Pulmonary 3 (0.1%) 10 (0.4%) 3.159embolism or deep [0.869-11.478] vein thrombosis Worsening 92 (4.0%) 78(3.4%) 0.805 heart failure, [0.595-1.089] including pulmonary edema ordyspnea of cardiac origin Ventricular 1 (<0.1%) 1 (<0.1%) 0.973extrasystoles [0.061-15.560] Ventricular 6 (0.3%) 6 (0.3%) 0.952tachycardia [0.307-2.951] (non-sustained and sustained) Ventricular 1(<0.1%) 1 (<0.1%) 0.943 fibrillation [0.059-15.083] Other ventricular 0(0%) 1 (<0.1%) NA arrhythmiaIII.31. Results Relating to the Prevention of CardiovascularHospitalization not Due to a Supraventricular Arrhythmia such as AtrialFibrillation or Flutter

Placebo Dronedarone (N = 2327) (N = 2301) HR (95% Cl) Any non-AF 511(22.0%) 438 (19.0%) 0.855 cardiovascular [0.753-0.972] hospitalizationAtherosclerosis 10 (0.4%) 11 (0.5%) 1.094 related (if not [0.464-2.575]otherwise specified) Myocardial 71 (3.1%) 52 (2.3%) 0.730 infarction[0.511-1.045] or unstable angina Stable angina 53 (2.3%) 51 (2.2%) 0.962pectoris [0.655-1.412] or atypical chest pain Syncope 28 (1.2%) 23(1.0%) 0.822 [0.474-1.427] TIA or stroke 43 (1.8%) 32 (1.4%) 0.742(except [0.469-1.172] intracranial hemorrhage) Non-fatal cardiac 2(<0.1) 3 (0.1%) 1.504 arrest [0.251-9.000] Cardiovascular 28 (1.2%) 24(1.0%) 0.853 surgery [0.495-1.472] except cardiac transplantationImplantation of a 56 (2.4%) 46 (2.0%) 0.819 pacemaker, [0.555-1.210] ICDor any other cardiac device Transcutaneous 40 (1.7%) 31 (1.3%) 0.773coronary, [0.484-1.235] cerebrovascular or peripheral procedure Bloodpressure 26 (1.1%) 25 (1.1%) 0.960 (hypotension, [0.554-1.662]hypertension, not syncope) Cardiovascular 0 (0%) 4 (0.2%) NA infectionMajor bleeding 28 (1.2%) 27 (1.2%) 0.960 (requiring two or [0.566-1.628]more units of blood or any intracranial hemorrhage) Pulmonary 4 (0.2%)11 (0.5%) 2.713 embolism or deep [0.864-8.521] vein thrombosis Worseningheart 113 (4.9%) 89 (3.9%) 0.787 failure, including [0.596-1.039]pulmonary edema or dyspnea of cardiac origin Ventricular 1 (<0.1) 1(<0.1) 1.005 extrasystoles [0.063-16.062] Ventricular 7 (0.3%) 6 (0.3%)0.857 tachycardia [0.288-2.550] (non-sustained and sustained)Ventricular 1 (<0.1) 1 (<0.1) 0.997 fibrillation [0.062-15.940] Otherventricular 0 (0%) 1 (<0.1) NA arrhythmia

For example, dronedarone was associated with a 14.5% reduction in therisk of a first cardiovascular hospitalization not due to asupraventricular arrhythmia (HR [95% CI] 0.855 [0.753-0.972]). As notedbelow, the lower number of non-AF/AFL hospitalizations on dronedaronewas mainly due to fewer hospitalizations for worsening heart failure, MIor unstable angina, or stroke or TIA.

1. An article of manufacture comprising a) a packaging material; b) dronedarone or a pharmaceutically acceptable salt thereof; and c) a label or package insert contained within the packaging material indicating that dronedarone or a pharmaceutically acceptable salt thereof is contraindicated in patients with severe heart failure.
 2. The article according to claim 1 wherein the packaging material indicates that that dronedarone or a pharmaceutically acceptable salt thereof is contraindicated in patients with severe heart failure indicated by one or more of the following: a) a history of, or current symptoms of congestive heart failure; b) symptoms of heart failure with minimal exertion within the last month; c) hospitalization of the patient for heart failure within the last month; d) hospitalization of the patient for NYHA Class IV heart failure; e) hospitalization of the patient for NYHA Class III heart failure within the last month; f) hospitalization of the patient for heart failure with recent decompensation as indicated by the need for hospitalization or intravenous therapy; and g) hospitalization of the patient for heart failure with recent decompensation requiring hospitalization or intravenous therapy for the treatment of heart failure.
 3. The article according to claim 1 wherein the packaging material indicates that dronedarone or a pharmaceutically acceptable salt thereof is contraindicated in patients with severe heart failure indicated by hospitalization of the patient for NYHA Class IV heart failure.
 4. The article according to claim 1 wherein the packaging material indicates that dronedarone or a pharmaceutically acceptable salt thereof is contraindicated in patients with severe heart failure indicated by hospitalization of the patient for NYHA Class III heart failure within the last month.
 5. A package comprising dronedarone or a pharmaceutically acceptable salt thereof and a label, said label comprising a printed statement which informs a prospective user that dronedarone or a pharmaceutically acceptable salt thereof is contraindicated in patients with severe heart failure.
 6. The package according to claim 5 wherein the printed statement informs a prospective user of one or more of the following: a) that dronedarone or a pharmaceutically acceptable salt thereof is contraindicated in patients with severe heart failure indicated by a history of, or current symptoms of congestive heart failure; b) that dronedarone or a pharmaceutically acceptable salt thereof is contraindicated in patients with severe heart failure indicated by symptoms of heart failure with minimal exertion within the last month; c) that dronedarone or a pharmaceutically acceptable salt thereof is contraindicated in patients with severe heart failure indicated by hospitalization for heart failure within the last month; d) that dronedarone or a pharmaceutically acceptable salt thereof is contraindicated in patients with severe heart failure indicated by NYHA Class IV; e) that dronedarone or a pharmaceutically acceptable salt thereof is contraindicated in patients with severe heart failure indicated by NYHA Class III within the last month; f) that dronedarone or a pharmaceutically acceptable salt thereof is contraindicated in patients with severe heart failure indicated by recent decompensation as indicated by the need for hospitalization or intravenous therapy; and g) dronedarone or a pharmaceutically acceptable salt thereof is contraindicated in patients who were hospitalized for heart failure with recent decompensation requiring hospitalization or intravenous therapy for the treatment of heart failure.
 7. A package comprising dronedarone or a pharmaceutically acceptable salt thereof and a label, said label comprising at least one message selected from the group consisting of: a) a primary endpoint of a study of dronedarone, or a pharmaceutically acceptable salt thereof, was the time to first hospitalization for cardiovascular reasons or death from any cause; b) a secondary endpoint of a study of dronedarone, or pharmaceutically acceptable salt thereof, was death from any cause; c) a secondary endpoint of a study of dronedarone, or a pharmaceutically acceptable salt thereof, was time to death from any cause; d) a secondary endpoint of a study of dronedarone, or a pharmaceutically acceptable salt thereof, was time to cardiovascular death; e) a secondary endpoint of a study of dronedarone, or a pharmaceutically acceptable salt thereof, was time to first hospitalization for cardiovascular reasons; f) a secondary endpoint of a study of dronedarone, or a pharmaceutically acceptable salt thereof, was time to first hospitalization for atrial fibrillation and other supraventricular rhythm disorders; g) a secondary endpoint of a study of dronedarone, or a pharmaceutically acceptable salt thereof, was time to first hospitalization for worsening heart failure; h) a secondary endpoint of a study of dronedarone, or a pharmaceutically acceptable salt thereof, was time to first hospitalization for myocardial infarction; i) a secondary endpoint of a study of dronedarone, or a pharmaceutically acceptable salt thereof, was time to first hospitalization for myocardial infarction; j) a secondary endpoint of a study of dronedarone, or a pharmaceutically acceptable salt thereof, was time to first hospitalization for transient ischemic event or cerebral stroke; and k) a secondary endpoint of a study of dronedarone, or a pharmaceutically acceptable salt thereof, was time to sudden death.
 8. A package comprising dronedarone or a pharmaceutically acceptable salt thereof and a label, said label comprising at least one message selected from the group consisting of: a) dronedarone, or a pharmaceutically acceptable salt thereof, reduced the combined endpoint of cardiovascular hospitalization or death from any cause by about 24 percent; b) dronedarone, or a pharmaceutically acceptable salt thereof, reduced the combined endpoint of cardiovascular hospitalization or death from any cause by 24.2 percent; c) dronedarone, or a pharmaceutically acceptable salt thereof, reduced the combined endpoint of cardiovascular hospitalization or death from any cause by 24.2 percent, driven by a reduction in cardiovascular hospitalization; d) the total duration of hospitalization was lower with dronedarone when compared to placebo; e) patients with NYHA Class III heart failure at baseline showed a reduction in cardiovascular hospitalization or death; and f) the risk of hospitalization for heart failure was less in the dronedarone group, or a pharmaceutically acceptable salt thereof, when compared to the placebo group. 